AD-related Dementias Research Articles

The African Initiative for Bioinformatics Online Training in Neurodegenerative Diseases (AI‐BOND): Investing in the next generation of African neuroscientists

AbstractNeurodegenerative disorders, including Alzheimer's disease and AD‐related dementias (AD/ADRD), pose significant challenges to health care systems globally, particularly in Africa. With the advances in medical technology and research capabilities, especially in next‐generation sequencing and imaging, vast amounts of data have been generated from AD/ADRD research. Given that the greatest increase in AD/ADRD prevalence is expected to occur in Africa, it is critical to establish comprehensive bioinformatics training programs to help African scientists leverage existing data and collect additional information to untangle AD/ADRD heterogeneity in African populations. The South Texas Alzheimer's Disease Research Center, with efforts from the National Institutes of Health and the Global Brain Health Institute, has partnered with the Brain Research Africa Initiative to develop the African Initiative on Bioinformatics Online Training in Neurodegenerative Disease (AI‐BOND). AI‐BOND is a comprehensive and accessible training program, the aim of which is to advance biostatistics and bioinformatics expertise in Africa in studying neurodegenerative diseases. This expertise is essential to enable African scientists to utilize the extensive AD/ADRD data and enhance the continent's ability to contribute to global research efforts in this field. The training addresses the gap in analyzing neurodegenerative disease data by providing skills and knowledge in genetic epidemiology, biostatistics, and bioinformatics to African students and researchers. This innovative online training program will last 6 months and provide training in skill sets R, SAS, and Python programing, genome‐wide association studies, genomics, transcriptomics, proteomics, metabolomics, microbiome analysis, and advanced statistical methods. Additional training will include study design and manuscript and grant writing. The first cohort of the AI‐BOND program will graduate in June 2024. The AI‐BOND program is expected to build research computational capacities in Africa that will improve the ability of graduates to conduct and utilize large‐scale studies, with the goal of curbing the growing incidence of neurodegenerative diseases in Africa.Highlights Alzheimer's disease (AD) and AD‐related dementias (ADRD) pose significant health challenges globally, particularly in Africa. The most significant AD/ADRD prevalence increase is predicted to occur in Africa. It is crucial to establish a bioinformatics training capacity in Africa to leverage the vast number of multi‐omics and imaging biomarkers of AD/ADRD data being generated. The African Initiative on Bioinformatics Online Training in Neurodegenerative Disease (AI‐BOND) training addresses the gaps in study design, biostatistics, genetic epidemiology, and bioinformatics related to neurodegenerative diseases in Africa. The success of AI‐BOND is anticipated to help build computational research capacities in Africa.

Discontinuing the Term “Stakeholder” From the NIA IMPACT Collaboratory Engaging Partners Team: An Example of the Process of Language Change in an Organization

In this paper, we describe our process of changing language of the National Institute on Aging Imbedded Pragmatic Alzheimer's disease and AD-related dementias Clinical Trials Collaboratory (NIA IMPACT Collaboratory) “Stakeholder Engagement Team” to “Engaging Partners Team” in response to feedback from community partners regarding the problematic connotations of the term “stakeholder.” We present a brief history of the term “stakeholder” and its use in clinical and community-engaged research. Then, we summarize critiques of this term, including its colonial history and potential to reinforce complacency with generational traumas, particularly among Indigenous peoples and communities. We conclude with a detailed overview of our team and organization's multi-step process to discontinue use of the term “stakeholder,” in alignment with a theoretical model of organizational behavior change. This paper highlights the importance of critically evaluating language and responding to community partners. We hope our process can guide other researchers and organizations.

Factors Affecting Resilience and Prevention of Alzheimer's Disease and Related Dementias.

Alzheimer's disease (AD) is a devastating, age-associated neurodegenerative disorder and the most common cause of dementia. The clinical continuum of AD spans from preclinical disease to subjective cognitive decline, mild cognitive impairment, and dementia stages (mild, moderate, and severe). Neuropathologically, AD is defined by the accumulation of amyloid β (Aβ) into extracellular plaques in the brain parenchyma and in the cerebral vasculature, and by abnormally phosphorylated tau that accumulates intraneuronally forming neurofibrillary tangles (NFTs). Development of treatment approaches that prevent or even reduce the cognitive decline because of AD has been slow compared to other major causes of death. Recently, the United States Food and Drug Administration gave full approval to 2 different Aβ-targeting monoclonal antibodies. However, this breakthrough disease modifying approach only applies to a limited subset of patients in the AD continuum and there are stringent eligibility criteria. Furthermore, these approaches do not prevent progression of disease, because other AD-related pathologies, such as NFTs, are not directly targeted. A non-mutually exclusive alternative is to address lifestyle interventions that can help reduce the risk of AD and AD-related dementias (ADRD). It is estimated that addressing such modifiable risk factors could potentially delay up to 40% of AD/ADRD cases. In this review, we discuss some of the many modifiable risk factors that may be associated with prevention of AD/ADRD and/or increasing brain resilience, as well as other factors that may interact with these modifiable risk factors to influence AD/ADRD progression. ANN NEUROL 2024.

Single-nucleus multiome analysis of human cerebellum in Alzheimer's disease-related dementia.

Although human cerebellum is known to be neuropathologically impaired in Alzheimer's disease (AD) and AD-related dementias (ADRD), the cell type-specific transcriptional and epigenomic changes that contribute to this pathology are not well understood. Here, we report single-nucleus multiome (snRNA-seq and snATAC-seq) analysis of 103,861 nuclei isolated from cerebellum from 9 human cases of AD/ADRD and 8 controls, and with frontal cortex of 6 AD donors for additional comparison. Using peak-to-gene linkage analysis, we identified 431,834 significant linkages between gene expression and cell subtype-specific chromatin accessibility regions enriched for candidate cis-regulatory elements (cCREs). These cCREs were associated with AD/ADRD-specific transcriptomic changes and disease-related gene regulatory networks, especially for RAR Related Orphan Receptor A (RORA) and E74 Like ETS Transcription Factor 1 (ELF1) in cerebellar Purkinje cells and granule cells, respectively. Trajectory analysis of granule cell populations further identified disease-relevant transcription factors, such as RORA, and their regulatory targets. Finally, we prioritized two likely causal genes, including Seizure Related 6 Homolog Like 2 (SEZ6L2) in Purkinje cells and KAT8 Regulatory NSL Complex Subunit 1 (KANSL1) in granule cells, through integrative analysis of cCREs derived from snATAC-seq, genome-wide AD/ADRD loci, and Hi-C looping data. This first cell subtype-specific regulatory landscape in the human cerebellum identified here offer novel genomic and epigenomic insights into the neuropathology and pathobiology of AD/ADRD and other neurological disorders if broadly applied.

Protocol for a telephonic mixed methods study to understand needs and find solutions for bereaved dementia caregivers

IntroductionMost caregivers of people living with dementia will experience bereavement within 10 years, but study of and support for their needs rarely persists following the death of their care recipients....

Antidepressant exposure and long-term dementia risk in a nationwide retrospective study on US veterans with midlife major depressive disorder.

The use of antidepressants in major depressive disorder (MDD) has been reported to influence long-term risk of Alzheimer's disease (AD) and AD-related dementias (AD/ADRD), but studies are conflicting. We used inverse probability weighted (IPW) Cox models with time-varying covariates in a retrospective cohort study among midlife veterans with MDD within the US Veterans Affairs healthcare system from January 1, 2000 to June 1, 2022. A total of 35,200 patients with MDD were identified. No associations were seen regarding the effect of being exposed to any antidepressant versus no exposure on AD/ADRD risk (events=1,056, hazard ratio=0.94, 95% confidence interval: 0.81 to 1.09) or the exposure to specific antidepressant classes versus no exposure. A risk reduction was observed for female patients in a stratified analysis; however, the number of cases was small. Our study suggests that antidepressant exposure has no effect on AD/ADRD risk. The association in female patients should be interpreted with caution and requires further attention. We studied whether antidepressant use was associated with future dementia risk. We specifically focused on patients after their first-ever diagnosis of depression. We used IPW Cox models with time-varying covariates and a large observation window. Our study did not identify an effect of antidepressant use on dementia risk. A risk reduction was observed in female patients, but the number of cases was small.

Characterization of monoamine oxidase-B (MAO-B) as a biomarker of reactive astrogliosis in Alzheimer’s disease and related dementias

Reactive astrogliosis accompanies the two neuropathological hallmarks of Alzheimer’s disease (AD)—Aβ plaques and neurofibrillary tangles—and parallels neurodegeneration in AD and AD-related dementias (ADRD). Thus, there is growing interest in developing imaging and fluid biomarkers of reactive astrogliosis for AD/ADRD diagnosis and prognostication. Monoamine oxidase-B (MAO-B) is emerging as a target for PET imaging radiotracers of reactive astrogliosis. However, a thorough characterization of MAO-B expression in postmortem control and AD/ADRD brains is lacking. We sought to: (1) identify the primary cell type(s) expressing MAO-B in control and AD brains; (2) quantify MAO-B immunoreactivity in multiple brain regions of control and AD donors as a proxy for PET radiotracer uptake; (3) correlate MAO-B level with local AD neuropathological changes, reactive glia, and cortical atrophy; (4) determine whether the MAOB rs1799836 SNP genotype impacts MAO-B expression level; (5) compare MAO-B immunoreactivity across AD/ADRD, including Lewy body diseases (LBD) and frontotemporal lobar degenerations with tau (FTLD-Tau) and TDP-43 (FTLD-TDP). We found that MAO-B is mainly expressed by subpial and perivascular cortical astrocytes as well as by fibrous white matter astrocytes in control brains, whereas in AD brains, MAO-B is significantly upregulated by both cortical reactive astrocytes and white matter astrocytes across temporal, frontal, and occipital lobes. By contrast, MAO-B expression level was unchanged and lowest in cerebellum. Cortical MAO-B expression was independently associated with cortical atrophy and local measures of reactive astrocytes and microglia, and significantly increased in reactive astrocytes surrounding Thioflavin-S+ dense-core Aβ plaques. MAO-B expression was not affected by the MAOB rs1799836 SNP genotype. MAO-B expression was also significantly increased in the frontal cortex and white matter of donors with corticobasal degeneration, Pick’s disease, and FTLD-TDP, but not in LBD or progressive supranuclear palsy. These findings support ongoing efforts to develop MAO-B-based PET radiotracers to image reactive astrogliosis in AD/ADRD.

Efficacy and safety of transcranial magnetic stimulation on cognition in mild cognitive impairment, Alzheimer's disease, Alzheimer's disease-related dementias, and other cognitive disorders: a systematic review and meta-analysis.

We aim to analyze the efficacy and safety of TMS on cognition in mild cognitive impairment (MCI), Alzheimer's disease (AD), AD-related dementias, and nondementia conditions with comorbid cognitive impairment. Systematic review, Meta-Analysis. We searched MEDLINE, Embase, Cochrane database, APA PsycINFO, Web of Science, and Scopus from January 1, 2000, to February 9, 2023. RCTs, open-label, and case series studies reporting cognitive outcomes following TMS intervention were included. Cognitive and safety outcomes were measured. Cochrane Risk of Bias for RCTs and MINORS (Methodological Index for Non-Randomized Studies) criteria were used to evaluate study quality. This study was registered with PROSPERO (CRD42022326423). The systematic review included 143 studies (n = 5,800 participants) worldwide, encompassing 94 RCTs, 43 open-label prospective, 3 open-label retrospective, and 3 case series. The meta-analysis included 25 RCTs in MCI and AD. Collectively, these studies provide evidence of improved global and specific cognitive measures with TMS across diagnostic groups. Only 2 studies (among 143) reported 4 adverse events of seizures: 3 were deemed TMS unrelated and another resolved with coil repositioning. Meta-analysis showed large effect sizes on global cognition (Mini-Mental State Examination (SMD = 0.80 [0.26, 1.33], p = 0.003), Montreal Cognitive Assessment (SMD = 0.85 [0.26, 1.44], p = 0.005), Alzheimer's Disease Assessment Scale-Cognitive Subscale (SMD = -0.96 [-1.32, -0.60], p < 0.001)) in MCI and AD, although with significant heterogeneity. The reviewed studies provide favorable evidence of improved cognition with TMS across all groups with cognitive impairment. TMS was safe and well tolerated with infrequent serious adverse events.

Abstract TP23: Differentiated Para-Vascular Distribution of Amyloid Plaques in Normal versus Cognitively Impaired

Introduction: The vascular contribution to Alzheimer’s disease (AD) and AD-related dementias is increasingly recognized. Scanning laser ophthalmoscopy (SLO) visualizes two important markers of cognitive dysfunction in the retina, vascular changes and amyloid plaque deposition. The relationship between retinal vascular changes and peri-vascular amyloid deposition in the continuum of neurodegeneration is imperfectly understood. In this exploratory topographic analysis of a cohort of subjects with normal and impaired cognition that underwent SLO, we investigated the retinal vascular-adjacent (para-vascular) amyloid plaque distribution and its correlation with cognitive measures. Methods: 34 subjects with cognitive decline underwent retinal SLO, brain magnetic resonance imaging and standard neuropsychometric testing. Retinal para-arteriolar and para-venular curcumin positive amyloid plaques were quantified in the supero-temporal retinal quadrant, in the first-, second- and third-order retinal vascular branches. The para-venous and para-arteriolar amyloid count were compared between patients with normal and impaired cognition, and their correlation with brain volumes and white matter hyperintensities was determined. Results: We analyzed retinal para-venous and para-arteriolar amyloid and vascular-structural parameters derived from 29 subjects, mean (SD) age 65(7), 48% female. Para-arteriolar plaque was higher than para-venular plaque in the entire cohort (p&lt;0.0001). Secondary branch para-venular amyloid plaque count was higher in patients with impaired cognition, CDR ≥1 and MOCA ≤26. The para-arterial plaque count in the secondary branches significantly correlated with hippocampal volume and white matter hyperintensities scores. Conclusion: Our topographic analysis of the amyloid plaque distribution in retinal para-vascular regions shows higher amyloid accumulation in the para-arteriolar regions overall, and specifically in the secondary para-venular branches in patients with impaired cognition. Larger longitudinal studies are needed to study the temporal and spatial relationship between vascular dysfunction and para-vascular amyloid deposition in AD.

Vascular Contributions to Healthy Aging and Dementia.

Vascular pathologies are among the most common contributors to neurodegenerative changes across the spectrum of normal aging to dementia. Cerebral small vessel disease (SVD) encompasses a wide range of conditions affecting capillaries, small arteries, and arterioles, as well as perivascular spaces and fluid dynamics in the brain, playing a significant role in vascular contributions to cognitive impairment and dementia (VCID). These factors can accelerate the progression of SVD and neuronal degeneration. Since aging is the primary risk factor for Alzheimer's disease (AD) and AD-related dementias (ADRD), this Research Topic aims to gather recent research to better understand vascular contributions to healthy aging and age-related cognitive impairment. Other risk factors include diabetes, lifestyle factors, high cholesterol, vascular inflammation, and immune remodeling, all of which can accelerate cognitive dysfunction progression. This special issue includes a total of 21 articles comprising Reviews, Perspectives, and Original Research articles. The articles cover various technical and biological aspects related to recent progress in aging and dementia research. We aim to promote research exchange across different fields, including imaging, VCID, molecular biology, neuroinflammation, and immunology. Most papers in this special issue focus on understanding the disease mechanisms of AD/ADRD and developing new therapeutic strategies.

Radiosynthesis and whole-body distribution in mice of a 18 F-labeled azepino[4,3-b]indole-1-one derivative with multimodal activity for the treatment of Alzheimer's disease.

Recently, the azepino[4,3-b]indole-1-one derivative 1 showed in vitro nanomolar inhibition against butyrylcholinesterase (BChE), the ChE isoform that plays a role in the progression and pathophysiology of Alzheimer's disease (AD), and protects against N-methyl- d-aspartate-induced neuronal toxicity. Three 9-R-substituted (R = F, Br, OMe) congeners were investigated. The 9-F derivative (2a) was found more potent asBChE inhibitors(half-maximal inhibitory concentration value = 21 nM) than 2b (9-Br) and 2c (9-OMe), achieving a residence time (38 s), assessed by surface plasmon resonance,threefold higher than that of 1. To progress in featuring the in vivo pharmacological characterization of 2a, herein the 18 F-labeled congener 2a was synthesized, by applying the aromatic 18 F-fluorination method, and its whole-body distribution in healthy mice, including brain penetration, was evaluated through positronemission tomographyimaging. [18 F]2a exhibited a rapid and high brain uptake (3.35 ± 0.26% ID g-1 at 0.95 ± 0.15 min after injection), followed by a rapid clearance (t1/2 = 6.50 ± 0.93 min), showing good blood-brain barriercrossing. After a transient liver accumulation of [18 F]2a, the intestinal and urinary excretion was quantified. Finally, ex vivo pharmacological experiments in mice showed that the unlabeled 2a affects the transmitters' neurochemistry, which might be favorable to reverse cognition impairment in mild-to-moderate AD-related dementias.

BUILDING BRIDGES, CATALYZING RESEARCH, EMPOWERING ALL AGES: A CHAT WITH NIA SENIOR LEADERSHIP

Abstract The National Institute on Aging (NIA) at the National Institutes of Health, Department of Health and Human Services, is the federally designated lead agency on aging research and supports research to understand the nature of aging and to extend the healthy, active years of life. Over the last decade, NIA’s budget has increased substantially. In keeping with NIA’s scientific mission, funding includes significant investments in Alzheimer’s disease (AD) and AD-related dementias research, as well as in non-AD research. This symposium will provide a forum for exploration of the implications of the NIA budget for the general research community. NIA’s senior staff will discuss research priorities and programs supported by the Institute. A question-and-answer session will follow these remarks on current funding and future priorities and research directions of NIA.

Understanding the molecular basis of resilience to Alzheimer's disease.

The cellular and molecular distinction between brain aging and neurodegenerative disease begins to blur in the oldest old. Approximately 15-25% of observations in humans do not fit predicted clinical manifestations, likely the result of suppressed damage despite usually adequate stressors and of resilience, the suppression of neurological dysfunction despite usually adequate degeneration. Factors during life may predict the clinico-pathologic state of resilience: cardiovascular health and mental health, more so than educational attainment, are predictive of a continuous measure of resilience to Alzheimer's disease (AD) and AD-related dementias (ADRDs). In resilience to AD alone (RAD), core features include synaptic and axonal processes, especially in the hippocampus. Future focus on larger and more diverse cohorts and additional regions offer emerging opportunities to understand this counterforce to neurodegeneration. The focus of this review is the molecular basis of resilience to AD.

Developing Topics.

Goal 1 of the National Plan to Address Alzheimer's Disease (AD) is to prevent and effectively treat AD and AD-related dementias (ADRD) by 2025. Toward this goal, NINDS plans 14 ADRD funding opportunities for 2024 to support training, basic mechanisms, translational, and clinical research for ADRD. Here, we describe ADRD translational therapy development initiatives, which include 1) multi-target validation, 2) early-stage therapy development, 3) genome editing and 4) animal model development and validation. Note, ADRD specific funding opportunities are not required. ADRD researchers can also take advantage of NINDS existing programs such as the NIH Blueprint for Neurotherapeutics (BPN) for Small Molecule or Biologic therapy development. These programs support optimization, manufacture, IND-enabling studies and first in human clinical trials through a combination of grants and complementary access to NIH-provided CROs and consultants. All concepts discussed here are approved, however NIH cannot guarantee future funding opportunities, award mechanisms, or funding allocation. A funding opportunity is only official when published in the NIH Guide. Multi-Target Validation for ADRD concept has the goal to support research that would validate multiple targets for future therapy development that better reflect the complexity of disease. Early-Stage Therapy Development concept would support the development of small molecule or biologic therapeutics and would be a reissue of RFA-NS-22-059, which supported assay development, therapeutic screening, optimization, and in vivo efficacy work in preparation for later-stage programs. Genome Editing for ADRD concept would support early translational research focused on somatic cell gene editing with the expectation that studies will address feasibility of the gene editing approach and would be a reissue of RFA-NS-23-017. PAR-23-154 "Development and Validation of Models for Alzheimer's Disease-Related Dementias (ADRD)" supports the development and validation of clinically- and pathophysiologically-relevant models of ADRD that can be used for future therapy development. Models should reflect multiple aspects of the human condition and include internal, face, construct, and predictive validation to the extent possible. Through these initiatives, NINDS hopes to provide a comprehensive pipeline for ADRD therapy development from target validation to the clinic.

Metabolic Syndrome‐Associated Oligodendrocyte Dysfunction and Cognitive Impairment

AbstractBackgroundOne in nine people aged 65 and older in the United States suffer from cognitive decline, including dementias such as Alzheimer’s disease (AD) and AD‐related Dementias (ADRD). A major risk factor for cognitive impairment is midlife metabolic syndrome (MetS). MetS‐associated cognitive impairment progresses in a non‐cell autonomous manner and implicates a breakdown in metabolic support. This breakdown in metabolic support is likely due to disruption of metabolic crosstalk between neurons and glia, especially oligodendrocytes. Our aim was therefore to elucidate midlife MetS effects on oligodendrocytes and subsequent impact on oligodendrocyte metabolism and cognition.MethodTo accomplish this aim, middle‐aged mice (12‐month old) were fed either standard diet (SD, 10% fat) or high‐fat diet (HFD, 60% fat) for 13 weeks, followed by full assessment of metabolic parameters and cognitive function. Oligodendrocytes were then isolated for single cell RNA‐sequencing (scRNA‐seq), and protein expression of monocarboxylate transporters (MCTs).ResultWe observed that, as expected, HFD mice gained more weight and had higher blood glucose and fat mass versus SD controls. Middle‐aged HFD mice also performed worse in puzzle box and social recognition tests, reflecting impaired executive function and impaired short‐ and long‐term memory responses. scRNA‐seq analysis identified multiple oligodendrocyte clusters. One cluster of interest contained genes involved in cognition (Fam171a2, Nrsn1, Dlgap4) and metabolism (Ldhb, Slc25a5, Cox7c, Cox17), which were differentially expressed in HFD versus SD mice. This was coupled with downregulated MCT1 protein expression in HFD mouse oligodendrocytes versus oligodendrocytes from their SD counterparts. In vitro, human oligodendrocytes treated with palmitate to mimic MetS developed insulin resistance and had downregulated MCT1 protein expression.ConclusionCollectively, these results suggest that midlife MetS impairs oligodendrocyte metabolic function, suggesting a novel mechanism underlying MetS‐associated cognitive impairment.

Investigating the role of structural variants in Alzheimer’s Disease and AD‐Related traits

AbstractBackgroundAlthough recent advances have led to a greater understanding of the genetics of Alzheimer’s Disease (AD), there remains a discrepancy between the predicted and observed genetic heritability estimates when using single nucleotide polymorphisms (SNPs) and small indel data. Large genomic rearrangements, known as structural variants (SVs), have the potential to account for this missing genetic heritability.MethodHere, we investigate the role of SVs in AD and AD‐related dementias (ADRD) by leveraging data from two ongoing cohort studies of aging and dementia, the Religious Orders Study and Rush Memory and Aging Project (ROS/MAP). We analyzed over 25,000 SVs discovered using whole genome sequencing (WGS) data of 1,106 participants and tested for association with multiple indices for AD/ADRD, including measurements of cognitive decline, amyloid beta, neuronal neurofibrillary tangles, TDP‐43, cerebral amyloid angiopathy, and resilience.ResultOur findings revealed five associations reaching genome‐wide significance. These included a 106 bp insertion (chr21:17,134,448; MAF = 0.01), located in the intronic region of the gene USP25, associated with a higher TDP‐43 burden (P‐value = 1.83×10−6). An 82 bp insertion at chr19:45,444,699 (MAF = 0.25), previously mapped as eQTL for APOC1 and sQTL for APOC2 in brain tissues, was linked to greater cerebral amyloid angiopathy (P‐value = 1.02×10−6). An 820 bp deletion chr15:26,003,040 (MAF = 0.031) overlapping a CTCF site near ATP10A was associated with greater odds of Lewy Body disease (P‐value = 1.03×10−6). A 55 bp insertion (chr12:131,797,376; MAF = 0.21) in an intergenic region was found to be associated with reduced vascular disease burden (P‐value = 2.96×10−7); and a 53 bp insertion (chr4:99,901,557; MAF = 0.014) mapped as protein QTL for ADH5 was linked to lower cognitive resilience (P‐value = 8.51×10−7).ConclusionThese findings provide evidence that common genetic variation, particularly SVs, can play a significant role in AD/ADRD traits. We are now investigating the functional impact of these SVs by integrating multi‐omics assays available from brain tissues of the same individuals. Our goal is to connect genetics to phenotype and gain a deeper understanding of the role of SVs in AD/ADRD.

Quantitative estimate of cognitive resilience and its medical and genetic associations

BackgroundWe have proposed that cognitive resilience (CR) counteracts brain damage from Alzheimer’s disease (AD) or AD-related dementias such that older individuals who harbor neurodegenerative disease burden sufficient to cause dementia remain cognitively normal. However, CR traditionally is considered a binary trait, capturing only the most extreme examples, and is often inconsistently defined.MethodsThis study addressed existing discrepancies and shortcomings of the current CR definition by proposing a framework for defining CR as a continuous variable for each neuropsychological test. The linear equations clarified CR’s relationship to closely related terms, including cognitive function, reserve, compensation, and damage. Primarily, resilience is defined as a function of cognitive performance and damage from neuropathologic damage. As such, the study utilized data from 844 individuals (age = 79 ± 12, 44% female) in the National Alzheimer’s Coordinating Center cohort that met our inclusion criteria of comprehensive lesion rankings for 17 neuropathologic features and complete neuropsychological test results. Machine learning models and GWAS then were used to identify medical and genetic factors that are associated with CR.ResultsCR varied across five cognitive assessments and was greater in female participants, associated with longer survival, and weakly associated with educational attainment or APOE ε4 allele. In contrast, damage was strongly associated with APOE ε4 allele (P value < 0.0001). Major predictors of CR were cardiovascular health and social interactions, as well as the absence of behavioral symptoms.ConclusionsOur framework explicitly decoupled the effects of CR from neuropathologic damage. Characterizations and genetic association study of these two components suggest that the underlying CR mechanism has minimal overlap with the disease mechanism. Moreover, the identified medical features associated with CR suggest modifiable features to counteract clinical expression of damage and maintain cognitive function in older individuals.

Cardiovascular Disease and Alzheimer's Disease: The Heart-Brain Axis.

Cardiovascular disease (CVD) remains one of the leading causes of morbidity and mortality in aging adults across the United States. Prior studies indicate that the presence of atherosclerosis, the pathogenic basis of CVD, is linked with dementias. Alzheimer's disease (AD) and AD-related dementias are a major public health challenge in the United States. Recent studies indicate that ≈3.7 million Americans ≥65 years of age had clinical AD in 2017, with projected increases to 9.3 million by 2060. Treatment options for AD remain limited. Development of disease-modifying therapies are challenging due, in part, to the long preclinical window of AD. The preclinical incubation period of AD starts in midlife, providing a critical window for identification and optimization of AD risk factors. Studies link AD with CVD risk factors such as hypertension, inflammation, and dyslipidemia. Both AD and CVD are progressive diseases with decades-long development periods. CVD can clinically manifest several years earlier than AD, making CVD and its risk factors a potential predictor of future AD. The current review focuses on the state of literature on molecular and metabolic pathways modulating the heart-brain axis underlying the potential association of midlife CVD risk factors and their effect on AD and related dementias. Further, we explore potential CVD/dementia preventive strategies during the window of opportunity in midlife and the future of research in the field in the multiomics and novel biomarker use era.

Explainable variational autoencoder (E-VAE) model using genome-wide SNPs to predict dementia

ObjectiveAlzheimer’s disease (AD) and AD related dementias (ADRD) are complex multifactorial neurodegenerative diseases. The associations between genetic variants obtained from genome wide association studies (GWAS) are the most widely available and well documented variants associated with ADRD. Application of deep learning methods to analyze large scale GWAS data may be a powerful approach to elucidate the biological mechanisms in ADRD compared to penalized regression models that may lead to over-fitting. MethodsWe developed a deep learning frame work explainable variational autoencoder (E-VAE) classifier model using genotype (GWAS SNPs = 5474) data from 2714 study participants in the Health and Retirement Study (HRS) to classify ADRD. We validated the generalizability of this model among 234 participants in the Religious Orders Study and Memory and Aging Project (ROSMAP). Utilizing a linear decoder approach we have extracted the weights associated with latent features for biological interpretation. ResultsWe obtained a predictive accuracy of 0.71 (95 % CI [0.59, 0.84]) with an AUC of 0.69 in the HRS test dataset and got an accuracy of 0.62 (95 % CI [0.56, 0.68]) with an AUC of 0.63 in the ROSMAP dataset. ConclusionThis is the first study showing the generalizability of a deep learning prediction model for dementia using genetic variants in an independent cohort. The latent features identified using E-VAE can help us understand the biology of AD/ ADRD and better characterize disease status.

Association of type 2 diabetes mellitus with dementia-related and non-dementia-related mortality among postmenopausal women: A secondary competing risks analysis of the women's health initiative.

Alzheimer's disease (AD) and AD-related dementias (ADRD) are leading causes of death among older adults in the United States. Efforts to understand risk factors for prevention are needed. Participants (n=146,166) enrolled in the Women's Health Initiative without AD at baseline were included. Diabetes status was ascertained from self-reported questionnaires and deaths attributed to AD/ADRD from hospital, autopsy, and death records. Competing risk regression models were used to estimate the cause-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for the prospective association of type 2 diabetes mellitus (T2DM) with AD/ADRD and non-AD/ADRD mortality. There were 29,393 treated T2DM cases and 8628 AD/ADRD deaths during 21.6 (14.0-23.5) median (IQR) years of follow-up. Fully adjusted HRs (95% CIs) of the association with T2DM were 2.94 (2.76-3.12) for AD/ADRD and 2.65 (2.60-2.71) for the competing risk of non-AD/ADRD mortality. T2DM is associated with AD/ADRD and non-AD/ADRD mortality. Type 2 diabetes mellitus is more strongly associated with Alzheimer's disease (AD)/AD and related dementias (ADRD) mortality compared to the competing risk of non-AD/ADRD mortality among postmenopausal women. This relationship was consistent for AD and ADRD, respectively. This association is strongest among participants without obesity or hypertension and with younger age at baseline, higher diet quality, higher physical activity, higher alcohol consumption, and older age at the time of diagnosis of type 2 diabetes mellitus.